Electrical stimulation in normal and retinal degeneration (rd1) isolated mouse retina

Stimulus threshold and response latencies were measured for electrically elicited retinal ganglion cell responses in retina isolated from the eyes of normal and retinal degenerate (rd1) mice. Stimulation of the ganglion cell-side in normal retina yielded a significantly lower mean threshold and shorter latency when compared with stimulation of the photoreceptor side in normal retina. The latency of the ganglion cell-side stimulation in normal retina also proved to be significantly shorter than the latency for stimulation of the ganglion cell side in rd1 retina. Thus both the electrode positioning as well as the health of the retinal tissue play a role in the stimulating current required to elicit a retinal response.     

Epidermal effects of tretinoin and isotretinoin: influence of isomerism

The efficacy of tretinoin is well established in the treatment of acne and photoaged skin, however as a typical side effect of tretinoin treatment most patients develop a low-grade irritant dermatitis. Since isotretinoin topical treatment usually shows much lower incidence and intensity of adverse effects than tretinoin topical treatment, histological studies are needed to scientifically evaluate the effects of isotretinoin application on epidermis and also to assess if it can be used in anti-aging products as an alternative to tretinoin. Thus, the aim of this study was to compare the effects of topical use of tretinoin or isotretinoin on hairless mice epidermis, using appropriate histopathological and histometric techniques, in order to evaluate the influence of isomerism on skin effects. For this, gel cream formulations containing or not 0.05% tretinoin or 0.05% isotretinoin were applied in the dorsum of hairless mice, once a day for seven days. Histopathological evaluation, viable epidermal and horny layer thicknesses as well as the number of epidermal cell layers were determined. Our results showed that tretinoin and isotretinoin were effective in the enhancement of viable epidermis thickness and number of epidermal cell layers, suggesting that they could be used for stimulation of cellular renewal. However isomerism influenced skin effects since isotretinoin had more pronounced effects than tretinoin in viable epidermis. In addition only isotretinoin treatment enhanced horny layer thickness when compared to the gel cream treatment.     

Influence of sodium metabisulfite and glutathione on the stability of vitamin C in O/W emulsion and extemporaneous aqueous gel

Vitamin C exerts several functions on skin as collagen synthesis, depigmentant and antioxidant activity. Vitamin C is unstable in the presence of oxygen, luminosity, humidity, high temperatures and heavy metals, which presents a significant challenge to the development of cosmetic formulations. Therefore, the utilization of an effective antioxidant system is required to maintain the vitamin C stability. The purpose of this research work was to develop prototypes of cosmetic formulations, as O/W emulsion and extemporaneous aqueous gel, containing vitamin C and to evaluate the influence of sodium metabisulfite (SMB) and glutathione (GLT), as antioxidants, on the stability of the active substance. A HPLC stability-indicating method was developed and validated for this study and stability assays were performed in 90 and 26 days and storage conditions were 5.0+/-0.5, 24+/-2 and 40.0+/-0.5 degrees C. The HPLC stability-indicating method showed linearity (r(2)>0.99), specificity, R.S.D.<1.22% and accuracy/recovery ranging from 95.46 to 101.54%. Preparations with SMB or GLT and the antioxidant-free presented results statistically distinct, demonstrating the necessity of the antioxidant system addition. O/W emulsions with SMB or GLT retained the vitamin C content >90.38% stored at 5.0+/-0.5 and 24+/-2 degrees C. For the aqueous gel with SMB or GLT, the active substance concentration was maintained >94.03%. Considering the vitamin C stability, the SMB and the GLT showed to be statistically adequate, as antioxidants, for the cosmetic formulations.     

High-dose-rate brachytherapy as part of a multidisciplinary treatment of nasopharyngeal lymphoepithelioma in childhood

BACKGROUND: Nasopharyngeal carcinoma in childhood is rare. Radiochemotherapy is considered the standard treatment and yields increased survival and local control rates. In this article, the authors report on the results from the multidisciplinary treatment of pediatric patients who had nasopharyngeal lymphoepithelioma with radiochemotherapy, including high-dose-rate brachytherapy of the primary tumor site. METHODS: Between May 1992 and May 2000, 16 children with nasopharyngeal lymphoepithelioma received neoadjuvant chemotherapy, conventional external beam radiotherapy, high-dose-rate brachytherapy, and adjuvant chemotherapy. Patients ranged in age from 7 years to 18 years, and 9 patients were male. Patient distribution according to clinical disease stage was as follows: Stage III, 1 patient; Stage IVA, 5 patients; Stage IVB, 9 patients; and Stage IVC, 1 patient. Three cycles of neoadjuvant and adjuvant chemotherapy in 3-week intervals were administered with cyclophosphamide, vincristine, doxorubicin, and cisplatin. The median doses of external beam radiotherapy to the primary tumor, positive lymph nodes, and subclinical areas of disease were 55 grays (Gy), 55 Gy, and 45 Gy, respectively. Children received 2 insertions of high-dose-rate brachytherapy at 5 Gy per insertion: These were performed with metallic applicators inserted through the transnasal access under local anesthesia. RESULTS: The median of follow-up was 54 months. At the time of last follow-up, 13 patients were alive without disease, 2 patients had died of disease, and 1 patient had died of treatment-related cardiac failure. Local control was achieved in 15 of 16 patients. Chemotherapy-related and radiotherapy-related acute toxicity was relevant but tolerable. CONCLUSIONS: In the current study, it was shown that the treatment was effective in the control of both local and distant disease, although there was relevant acute and late toxicity. High-dose-rate brachytherapy was deliverable on an outpatient basis with local anesthesia. Close follow-up of these patients was necessary to evaluate the significance of treatment-related late effects and their impact on quality of life.     

Gene expression profiling identifies BAX-delta as a novel tumor antigen in acute lymphoblastic leukemia

The identification of new tumor-associated antigens (TAA) is critical for the development of effective immunotherapeutic strategies, particularly in diseases like B-cell acute lymphoblastic leukemia (B-ALL), where few target epitopes are known. To accelerate the identification of novel TAA in B-ALL, we used a combination of expression profiling and reverse immunology. We compared gene expression profiles of primary B-ALL cells with their normal counterparts, B-cell precursors. Genes differentially expressed by B-ALL cells included many previously identified as TAA in other malignancies. Within this set of overexpressed genes, we focused on those that may be functionally important to the cancer cell. The apoptosis-related molecule, BAX, was highly correlated with the ALL class distinction. Therefore, we evaluated BAX and its isoforms as potential TAA. Peptides from the isoform BAX-delta bound with high affinity to HLA-A*0201 and HLA-DR1. CD8+ CTLs specific for BAX-delta epitopes or their heteroclitic peptides could be expanded from normal donors. BAX-delta-specific T cells lysed peptide-pulsed targets and BAX-delta-expressing leukemia cells in a MHC-restricted fashion. Moreover, primary B-ALL cells were recognized by BAX-delta-specific CTL, indicating that this antigen is naturally processed and presented by tumor cells. This study suggests that (a) BAX-delta may serve as a widely expressed TAA in B-ALL and (b) gene expression profiling can be a generalizable tool to identify immunologic targets for cancer immunotherapy.     

Outcome of Long‐Term Bisphosphonate Therapy in McCune‐Albright Syndrome and Polyostotic Fibrous Dysplasia

McCune‐Albright syndrome (MAS) is a rare bone disorder characterized by fibrous dysplasia (FD), endocrinopathies, and café‐au‐lait patches. FD patients have been shown to respond favorably to treatment with bisphosphonates, but data are scarce in the more severe polyostotic form (PFD), including MAS, and factors determining treatment outcome are not known, particularly in the long‐term. We evaluated the biochemical (bone turnover markers [BTMs]) and clinical (pain reduction) outcome of bisphosphonate therapy in 11 patients with MAS and 30 patients with PFD: median duration of treatment 6 years (range, 2 to 25 years). Prognostic factors for treatment outcome were identified in both groups. Patients with MAS were younger at diagnosis (p = 0.001), all had precocious puberty, and four (36%) had additional growth hormone (GH) excess associated with severe craniofacial FD. Extent of skeletal disease was more severe in MAS compared to PFD. MAS patients had higher serum alkaline phosphatase (ALP) concentrations (p = 0.005), higher skeletal burden scores (p < 0.001), and more fractures (p = 0.021). MAS patients had also higher levels of FGF‐23 (p = 0.008) and higher prevalence of hypophosphatemia (p = 0.013). Twenty‐four of 30 PFD patients (80%) demonstrated a complete clinical and biochemical response within a year of starting treatment (p = 0.015), compared to only four of 11 MAS patients (36%). There were no nonresponders. In the whole group, FGF‐23, total ALP, P1NP, and CTX positively correlated with skeletal burden scores (all p ≤ 0.001), which was the only significant risk factor for an incomplete response to bisphosphonate therapy (p < 0.01). Our data suggest a beneficial and safe outcome of long‐term bisphosphonate therapy in the majority of patients with PFD, although response to therapy was limited by the higher skeletal disease burden in MAS patients. In the PFD/MAS population studied, the only identified prognostic factor that influenced the outcome of bisphosphonate therapy was a high skeletal burden score. © 2016 American Society for Bone and Mineral Research.     

Impact Microindentation: Consistency of Serial Measurements and Alterations in Patients With Paget's Disease of the Tibia

Impact microindentation (IMI) is a new technique for the in vivo measurement of tissue‐level properties of cortical bone in humans. To address issues related to the proper application of IMI in clinical practice and to directly examine cortical bone properties in patients with tibia pathology, we studied 11 subjects without tibia pathology and nine patients with Paget's disease of the tibia in biochemical remission after bisphosphonate treatment. Serial indentations in the tibias of both legs were performed in all subjects by a single operator until 10 adequate measurements were obtained in each tibia. In patients without Paget's disease (7 men and 4 women; mean age, 61.9 years; range, 51 to 72 years), there was no difference in mean bone material strength index (BMSi) between the dominant and nondominant leg (82.1 ± 1.3 and 81.4 ± 1.3, respectively; p = 0.606). In each individual subject studied, sequential indentations in both legs showed no trends for higher or lower values with time. The standard deviation of unnormalized bone material strength (BMSu) was also comparable between the dominant and nondominant tibia (5.3 and 4.5, respectively; p = 0.657). In patients with Paget's disease (4 men and 5 women; mean age, 69.5 years; range, 55 to 87 years), mean BMSi of the Pagetic tibia was lower, albeit nonsignificantly, than that of the contralateral nonaffected tibia (74.7 ± 1.7 and 78.7 ± 1.3, respectively; p = 0.120). In contrast to subjects without Paget's disease, the SD of adequate BMSu values was significantly larger in the Pagetic tibia compared to that of the non‐Pagetic tibia (7.6 versus 5.0, respectively, p = 0.008). These results highlight the consistency of serial IMI measurements as performed by a single operator in the presence as well as absence of tibia pathology and illustrate that the method is able to capture alterations of tissue‐level cortical bone properties in patients with Paget's disease of the tibia. © 2017 The Authors.Journal of Bone and Mineral Research Published by Wiley Periodicals Inc.     

Echovirus 30 detection in an outbreak of acute myalgia and rhabdomyolysis,Brazil 2016–2017

Objectives

To describe an outbreak of acute myalgia accompanied by elevated levels of muscle enzymes that occurred in the northeast region of Brazil from December 2016 through to May 2017.

HIV-1 infection among injection and ex-injection drug users from Rio de Janeiro, Brazil: prevalence, estimated incidence and genetic diversity.

BACKGROUND AND OBJECTIVES: Due to their behavioral conditions and vulnerability, injection drug users (IDUs) are prone to multiple simultaneous or sequential infections with distinct HIV-1 subtypes and variants, making them a key population for molecular epidemiology surveillance. In the present study, we evaluated HIV-1 infection seroprevalence, genetic diversity and estimated incidence among IDUs and ex-injection drug users (ex-IDUs) from Rio de Janeiro, Brazil. STUDY DESIGN: Six hundred and eight IDUs and ex-IDUs, recruited between 1999 and 2001, were interviewed and agreed to donate 30 ml of blood. The serologic status for HIV infection was determined by two ELISAs and confirmed by IFA. CD4+ T-cell percentages were assessed by flow cytometry. HIV-1 positive samples were submitted to viral load quantification. DNA samples were PCR amplified and HIV-1 subtypes were determined using env and gag HMA. RESULTS AND CONCLUSIONS: Forty-eight (7.89%) individuals were seropositive for HIV-1 infection. The seroincidence of HIV-1 infection was estimated as 0.76%. HIV-1 env and gag subtyping identified 29 (69%) samples as belonging to subtype B, 7 (16.7%) to subtype F, and 6 (14.3%) discordant env/gag genomes infections, indicating the circulation of recombinant viruses in this population.     

Generalized glycogen storage and cardiomegaly in a knockout mouse model of Pompe disease

Glycogen storage disease type II (GSDII; Pompe disease), caused by inherited deficiency of acid alpha-glucosidase, is a lysosomal disorder affecting heart and skeletal muscles. A mouse model of this disease was obtained by targeted disruption of the murine acid alpha-glucosidase gene (Gaa) in embryonic stem cells. Homozygous knockout mice (Gaa -/-) lack Gaa mRNA and have a virtually complete acid alpha-glucosidase deficiency. Glycogen-containing lysosomes are detected soon after birth in liver, heart and skeletal muscle cells. By 13 weeks of age, large focal deposits of glycogen have formed. Vacuolar spaces stain positive for acid phosphatase as a sign of lysosomal pathology. Both male and female knockout mice are fertile and can be intercrossed to produce progeny. The first born knockout mice are at present 9 months old. Overt clinical symptoms are still absent, but the heart is typically enlarged and the electrocardiogram is abnormal. The mouse model will help greatly to understand the pathogenic mechanism of GSDII and is a valuable instrument to explore the efficacy of different therapeutic interventions.